Molecular Epidemiology of Primary CMV Infection

描述(申请人提供)：基于基因组差异检测的分子技术显示，许多CMV毒株在种群中传播。虽然传统上认为原发人类巨细胞病毒感染是由单一毒株引起的，但以前对巨细胞病毒株异质性的研究主要局限于器官移植受者。在这种情况下，分离出多个CMV毒株被认为是再感染的证据。研究表明，在临床环境和社区中，受试者(移植患者、艾滋病患者、日间托儿所的幼儿、性行为活跃的人)可能会随着时间的推移接触并再次感染多种巨细胞病毒株。以前没有研究确定健康受试者的初始CMV感染是否涉及多种毒株。对这一问题的兴趣源于我们之前的工作，在先天性CMV感染导致胎儿宫内死亡的胎儿中，我们鉴定了多种CMV毒株(基于UL144和US28基因)。从CMV感染的活体婴儿的培养分离株中只鉴定出一种基因型。根据文献，人们可能会认为这些严重的先天性巨细胞病毒感染是由于母亲的原发感染。然而，对多个菌株的检测表明，再次感染可能起到了一定作用。目前尚不清楚检测的差异是否与从组织中直接测序有关，而不是与从培养中选择优先菌株有关。本应用的目的是通过以下特定目的来表征健康成人原发CMV感染过程中的毒株异质性：1.基于UL144、UL146和糖蛋白B基因的序列多样性，确定健康成人原发CMV感染是单个毒株还是多个毒株。2.确定初次感染后6~12个月检出的巨细胞病毒株与初次感染时检出的株(S株)是否存在差异。这项探索性研究将有助于确定菌株多样性在多大程度上可以作为CMV再感染的证据。这可能会为更广泛的研究(从受试者数量、病毒排泄部位的数量、所研究的基因数量)在正常宿主中初次感染CMV的菌株多样性方面奠定基础。此外，这项研究将对疫苗开发和理解自然感染CMV如何导致对该病毒的广泛免疫具有重要意义。PHS 398/2590(Rev.05/01)第二页持续格式巨细胞病毒(巨细胞病毒)感染是最常见的由母亲传播给新生儿的感染，影响全球1%的新生儿。这种病毒的基因构成有几种变异，这些变异的专业术语是病毒株。这项应用的目标是确定急性CMV感染是由单一菌株还是由多个菌株引起，这是通过对各种体液进行基因测序技术确定的。这一应用将提高我们对急性CMV感染的认识，并将为疫苗开发开辟新的研究方向。。

DESCRIPTION (provided by applicant): Molecular techniques based on detection of genomic differences reveal that numerous CMV strains are circulating in the population. Although primary human CMV infection is traditionally believed to be caused by a single strain, previous studies of CMV strain heterogeneity have been limited mostly to organ transplant recipients. Outside this setting, isolation of multiple CMV strains has been considered proof of reinfection. Studies show that in both clinical settings and in the community, subjects (transplant patients, AIDS patients, young children in day care, sexually active persons) may be exposed to and re-infected over time with multiple CMV strains. No previous studies have determined whether initial CMV infection in healthy subjects involves multiple strains. Interest in this issue stems from our previous work in which we identified multiple CMV strains (based on UL144 and US28 genotypes) in fetuses who died in utero from congenital CMV infection. Only a single genotype was identified from cultured isolates of CMV infected live infants. Based on the literature, one would expect that these severe cases of congenital CMV infection were due to a primary maternal infection. However, the detection of multiple strains suggests that reinfection could have played a role. Whether the difference in detection is related to direct sequencing from tissue as opposed to selection of preferential isolates from culture is unclear. The goal of this application is to characterize strain heterogeneity during primary CMV infection in healthy adults through the following specific aims: 1. To determine whether primary CMV infection in healthy adults involves single strain or multiple strains based on sequence diversity in UL144, UL146 and glycoprotein B genes. 2. To determine whether CMV strains detected six to twelve months years after primary infection are different from the strain(s) detected at the time of initial infection. This exploratory study will help define the extent to which strain diversity can be used as evidence of CMV reinfection. It will likely lay the groundwork for a more extensive study (in terms of number of subjects, number of sites of viral excretion, number of genes studied) of strain diversity in primary CMV infection in the normal host. In addition this study will have significant implications for vaccine development and understanding how natural CMV infection leads to broad immunity to the virus. PHS 398/2590 (Rev. 05/01) Page 2 Continuation Format Page CMV (cytomegalovirus) infection is the most common infection transmitted from mothers to newborns, affecting 1 percent of newborns worldwide. There are several variations in the genetic makeup of the virus, and the professional term for those is viral strains. The goal of this application is to determine whether acute CMV infection is caused by a single strain or multiple strains, as determined using genetic sequencing techniques on a variety of bodily fluids. This application will improve our understanding of acute CMV infection and will open new research directions in vaccine development. .